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Pyridylpiperazine-based allosteric inhibitors of RND-type multidrug efflux pumps

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Plé, Coline | Tam, Heng-Keat | Vieira da Cruz, Anais | Compagne, Nina | Jiménez-Castellanos, Juan-Carlos | Müller, Reinke | Pradel, Elizabeth | Foong, Wuen Ee | Malloci, Giuliano | Ballée, Alexia | Kirchner, Moritz | Moshfegh, Parisa | Herledan, Adrien | Herrmann, Andrea | Deprez, Benoit | Willand, Nicolas | Vargiu, Attilio Vittorio | Pos, Klaas, M. | Flipo, Marion | Hartkoorn, Ruben, C.

Edité par CCSD ; Nature Publishing Group -

International audience. Efflux transporters of the RND family confer resistance to multiple antibiotics in Gram-negative bacteria. Here, we identify and chemically optimize pyridylpiperazine-based compounds that potentiate antibiotic activity in E. coli through inhibition of its primary RND transporter, AcrAB-TolC. Characterisation of resistant E. coli mutants and structural biology analyses indicate that the compounds bind to a unique site on the transmembrane domain of the AcrB L protomer, lined by key catalytic residues involved in proton relay. Molecular dynamics simulations suggest that the inhibitors access this binding pocket from the cytoplasm via a channel exclusively present in the AcrB L protomer. Thus, our work unveils a class of allosteric efflux-pump inhibitors that likely act by preventing the functional catalytic cycle of the RND pump.

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